Project Summary/Abstract We are excited to observe significant differences in the GPR109A levels in the white blood cells (macrophages) of Parkinson's disease (PD) patients and control individuals. Moreover, we observed similar changes in the GPR109A expressions in the substantia nigra regions that co-localize with the microglia of the PD patients and age-matched controls. We are the first lab to denote these changes. GPR109A is an anti- inflammatory receptor and niacin acts on it. Niacin is an anti-inflammatory agent and it is known to halt inflammation via GPR109A and nuclear factor-B (NFkB) pathway. Niacin is known to block the translocation of NFKB to nucleus and thus reduce the production of pro-inflammatory cytokines. We will study these effects of niacin in PD patients by analyzing inflammatory cytokines in the cerebrospinal fluid (CSF) of PD patients. It has been documented that PD patients who are on carbidopa treatment have decreased levels of niacin. We have found significant reduction in the niacin index (NAD/NADP ratio) in PD patients compared to age- matched controls, denoting reduced NAD levels and increased oxidative stress. We propose a novel hypothesis that by reducing inflammation, niacin treatment will restore niacin levels along with GPR109A levels and will help improve motor coordination and cognition performances in the PD patients. Specific Aims: The two specific aims of the current proposal are as follows: Aim 1 A: To determine whether niacin supplementation will improve the symptoms of PD patients as correlated by performances in motor coordination and cognitive tests. Aim 1 B: To determine whether up-regulation of GPR109A in PD patients will respond to niacin therapy in reducing inflammatory markers in the CSF. Aim 2: To study the molecular mechanisms related to GPR109A as an anti-inflammatory therapeutic target in in-vitro models.